Heart rhythm disturbances are the leading cause of sudden death in the United States, the treatment of cardiac arrhythmias remains a difficult challenge to physicians. The goal of this competitive renewal is to discover how arrhythmogenic interventions and antiarrhythmic drugs act and interact to affect fundamental active and passive cellular properties that ultimately determine abnormal cardiac excitability to produce abnormal cardiac excitability, lead to potentially lethal arrhythmias, and influence the treatment of these rhythm disturbances. Our earlier work suggested we test the following hypotheses: (1) an electrophysiologic matrix of active and passive cellular properties determines normal cardiac excitability; (2) the normal matrix must be altered by arrhythmogenic influences which affect one or more components of excitability to produce abnormal excitability and cardiac arrhythmias; and (3) the normal matrix or the matrix deformed by arrhythmogenic influences may interact with antiarrhythmic drugs, the predominant interaction differing depending on the matrix encountered, resulting in yet another matrical configuration. Conditions thought important in ischemia will be used to perturb the matrix including exposure to putative metabolites of ischemia such as lysophosphatidylcholine, free oxygen radicals and changes in the ionic milieu, pH, and oxygen. Important prototypic antiarrhythmic drugs will be studied alone and in the presence of these arrhythmogenic influences. Operationally, we aim to further develop this concept through experiments and modeling and to relate the concept to the clinical realities of arrhythmias and their treatment. Methodologically, we have used and developed powerful quantitative techniques in cardiac Purkinje fibers that utilize intracellular current application and voltage-clamping to assess overall excitability and the active and passive cellular properties that determine excitability. Some issues are best approached and will be studied using current- and voltage-clamping in isolated cells, such as the assessment of transmembrane currents, the actions of gap junctions, and the mechanisms of repolarization. The concept of altered excitability suggests new approaches to the classification of antiarrhythmic drugs and the treatment of cardiac arrhythmias.